Depressive Disorders
Depressive disorders are a class of psychiatric disorders classified under mood disorders, representing a condition with some disturbance in living activity due to a persistent depressive state. Regarding the classification and diagnosis of mood disorders, information is available in the American Psychiatric Association's “Diagnostic and Statistical Manual of Mental Disorders—IV: DSM-IV-TR” and the World Health Organization's “International Statistical Classification of Diseases and Related Health Problems—10: ICD-10, F30-F39”. According to the provisions of the DSM-IV-TR, mood disorders are roughly divided into bipolar disorders, which have both depressive symptoms and exaltation (manic symptoms), and depressive disorders, which involve depressive symptoms only. Bipolar disorders are classified into bipolar I disorders, which involve manic symptoms and depressive symptoms; bipolar II disorders, which involve depressive symptoms and mild manic symptoms; cyclothymic disorders, which involve mild depressive symptoms and mild manic symptoms; and bipolar disorders not otherwise specified. Depressive disorders are classified into major depressive disorders, in which a single depressive symptom is observed for 6 months or more; dysthymic disorders, in which mild depressive symptoms are observed for 2 years or more; and depression-related syndromes (minor depressive disorders, which are mildly symptomatic depressive disorders, recurrent short-term depressive disorders, in which short-term depressive symptoms are repeatedly observed, premenstrual dysphoric mood disorders, which are woman-specific physiological depressive symptoms). In addition to the aforementioned two major classes, mood disorders due to physical disorder, mood disorders due to drugs etc., mood disorders not otherwise specified and the like are classified under the category mood disorders as a whole.
Major Depressive Disorders (Major Depression)
Major depressive disorders are a disease commonly known as depression, representing a class of mood disorders. The essential feature thereof is that social activity is disturbed by long-lasting depressive symptoms. Patients with major depressive disorders can manifest common physical symptoms such as limb/back/head heaviness, back pain, headache, muscle pain, decreased physical strength, lassitude, and body weight loss. Also manifested are circulatory symptoms such as tachycardia; digestive symptoms such as dry mouth, dysgeusia, dyspepsia, diarrhea, abdominal pain, and anorexia; respiratory symptoms such as respiratory distress and hyperventilation; reproductive symptoms such as decreased libido and menstrual irregularities; urogenital symptoms such as pollakiuria and dysuria; and the like; the physical symptoms thereof encompass a broad range.
Dysthymic Disorders (Dysthymia)
Dysthymic disorders are a disease that was known as depressive hypomelancholia in the past, representing a class of mood disorders. The essential feature thereof is that social activity is disturbed by long-lasting depressive symptoms but the criteria of major depressive disorders are not met. Although dysthymic disorders involve relatively mild symptoms compared with major depressive disorders, such difference in the symptoms does not show in the degree of disturbance in social life, and both are the same in that the patients are in a pathological depressive state.
Depression-Related Syndrome
This is a syndrome proposed as defined by the DSM-IV-TR for a class that was known as mild depression in the past. Minor depressive disorders, which are mildly symptomatic depressive disorders; recurrent short-term depressive disorders, in which short-term depressive symptoms are repeatedly observed; premenstrual dysphoric mood disorders, which are woman-specific physiological depressive symptoms; and the like are included.
Mood Disorders Due to Physical Disorder (Depressive Symptoms Due to Physical Disorder)
There are some cases where depressive symptoms are manifested even when the underlying disease is not a mental disease but an internal medical disease, which are generically referred to as mood disorders due to physical disorder. Internal medical diseases include, for example, hypothyroidism, hyperparathyroidism, and Cushing's syndrome, which are endocrine diseases; systemic erythematodes and rheumatoid arthritis, which are collagen diseases; cerebral infarction and Parkinson's disease as organic cerebral diseases; infectious diseases such as by influenza or human immunodeficiency virus; and the like.
Mood Disorders Due to Drugs etc. (Drug-Induced Depressive Symptoms)
There are some cases where depressive symptoms are manifested with other drug therapies, and these are described as mood disorders due to drugs etc. Drugs known to induce depressive symptoms include, for example, reserpine, which is used as a hypotensive drug; methyl-dopa; clonidine; propranolol; hormones such as adrenocorticosteroid and progestin/estrogen mixed hormone; anti-Parkinsonian drugs such as L-dopa, amantadine hydrochloride, and bromocriptine; histamine H2 receptor antagonists such as cimetidine; interferons; cycloserine and the like.
Regarding depressive disorders, a wide variety of causes are suspected; in particular, genetic temperaments, growth and development in infancy and childhood, as well as combinations thereof with later life experiences are suspected. Depressive disorders are treated by using counseling, psychotherapy, pharmacological therapy (drug therapy) and the like singly or in combination. Drugs that are typically used to treat depressive disorder patients include, for example, tricyclic/tetracyclic antidepressants such as amitriptyline hydrochloride, imipramine hydrochloride, clomipramine hydrochloride, amoxapine, mianserin hydrochloride, maprotiline hydrochloride, and the like; selective serotonin reuptake inhibitors (SSRIs) such as paroxetine, fluvoxamine, fluoxetine, and the like; serotonin/noradrenaline uptake inhibitors (SNRIs) such as milnacipran, duloxetine, venlafaxine, and the like; and the like. Other drugs used include, for example, sulpiride, trazodone hydrochloride and the like.
On the other hand, it is known that adenosine is widely distributed in the whole body, and exhibits a variety of physiological actions on the central nervous system, the cardiac muscle, the kidneys, the smooth muscle, and the like through its receptors (see non-patent document 1).
For example, adenosine A1 antagonists are known to facilitate defecation (Jpn. J. Pharmacol., Vol.68, p.119 (1995)). Further, the adenosine A2A receptors are known to be involved particularly in the central nervous system, and the antagonists of the adenosine A2A receptors are known to be useful as, for example, therapeutic drugs for Parkinson's disease etc. (see non-patent document 2), therapeutic drugs for sleep disturbance (see Nature Neuroscience, p. 858 (2005); patent document 3), therapeutic drugs for depression (see non-patent document 3) and the like. There are many reports concerning the relationship between adenosine receptors and Parkinson's disease (Nature Reviews Drug Discovery, 5, p.845 (2006); Current Pharmaceutical Design, 14, p.1475 (2008)).
Regarding the association between adenosine A2A receptors and depressive symptoms, an investigation using mice deficient in adenosine A2A receptors led to a report that adenosine A2A receptor antagonistic activity induces behavioral pharmacological changes similar to those with administration of antidepressants (see Non-patent Document 4). Xanthine compounds having adenosine A2A receptor antagonistic activity are known to possess antidepressive activity (for example, WO94/01114), and are known to further possess anti-Parkinsonian activity (for example, Ann. Neurol., 43, p. 507 (1998)), therapeutic effects on anxiety disorders (for example, WO2004/108137), suppressing activity against neurodegeneration (for example, WO99/12546) and the like. Combinations of adenosine A2A receptor antagonists and antidepressants or anxiolytics have been reported (see Patent Document 1).
On the other hand, for example, compounds represented by the formulas (IA), (IB), (IC), (ID) and the like are known to have affinity to adenosine A2A receptors and have a therapeutic effect for Parkinson's disease (see patent document 2). It is also known that these compounds are useful as an agent for the treatment and/or prophylaxis of sleep disturbance (see patent document 3).
